NGS RASopathy Panel
This panel consists of 23 genes associated with various RASopathy disorders. Multisystem effects of alterations in the RAS-MAPK pathway lead to physiological and anatomical abnormalities including dysmorphic features, heart defects, short stature, skin lesions, and intellectual disability. Conditions associated with mutations in the RAS-MAPK pathway include:
Cardio-facio-cutaneous syndrome - Features of CFC syndrome include macrocephaly, cardiac abnormalities, short neck, ectodermal changes, and variable degrees of intellectual disability.
Costello syndrome - This condition is characterized by intellectual disability, failure to thrive, coarse facial features, loose skin, hyperextensibility, short stature, and heart defects. Papillomatous skin lesions in the oral, nasal, and anal regions are common.
LEOPARD syndrome - This disorder, also known as multiple lentigines syndrome, involves lentigines (pigmented skin lesions), cardiac rhythm abnormalities, hypertelorism, pulmonic stenosis, growth retardation, and deafness. Intellectual disability is common.
Noonan syndrome - Features of Noonan syndrome include short stature, a broad or webbed neck, low-set nipples, heart defects, and mild intellectual disability in approximately 1/3 of patients.
Neurofibromatosis - Individuals with Neurofibromatosis 1 (NF1) have two or more of the following findings: six or more cafe au laits spots, two or more neurofibromas or one plexiform neuroma, axial or inguinal freckling, Lisch nodules, optic glioma, specific skeletal findings, or an affected first-degree relative. This condition is relatively common, and it demonstrates a wide range of expressivity, even within the same family. Neurofibromatosis 2 (NF2) is a rare disorder characterized by acoustic neuromas and vestibular schwannomas that may affect hearing and balance. New mutations are responsible for approximately half of all cases.
Schwannomatosis - This condition includes non-vestibular schwannomas that are often associated with significant degrees of pain. Scwhannomas may be widespread or limited to a specific area of the body.
Legius syndrome - The phenotype of Legius syndrome may resemble that of Neurofibromatosis 1 with the exception of cafe au laits spots. Other dysmorphic features may or may not be present. This disorder is caused by mutations in SPRED1.
|Indications||Molecular testing is useful to confirm the diagnosis and to identify the disease causing mutations within a family to allow for carrier testing and prenatal diagnosis.|
|Detection||The current design of the RASopathy panel covers the coding region for all 23 genes and the flanking intronic sequences. This method allows for analysis of greater than 98% of the targeted sequence for the detection of nucleotide substitutions and small deletions and duplications. Large deletions and duplications will not be detected by this panel. Mutations and variants identified on the panel are confirmed with Sanger sequencing. All novel and apparently pathogenic changes are reported when found within the coding region as well as within 10 basepairs of each intron/exon boundary for each gene. Promoter and 3' untranslated sequences are not included in the current analysis. It should be noted that the current protocol is not specifically designed to detect copy number alterations and single exon deletions may require additional follow-up to determine whether or not they represent technical artifacts.
We recommend further array-based testing to more accurately address the concerns of dosage alterations. The Cytogenetic Laboratory at GGC offers a high resolution testing whole genome SNP microarray. The GGC Diagnostic Laboratory Directors are available for further consultation regarding the limitations of the NGS and array testing procedures.
The following genes can also be ordered as individual sequencing tests or tiered sequencing tests:
BRAF, MAP2K1 and MAP2K2, and KRAS (Tiered sequencing for CFC syndrome)
PTPN11, RAF1 selected exons, and BRAF (Tiered sequencing for LEOPARD syndrome)
PTPN11, SOS1, RAF1, KRAS, SHOC2(S2G mutation), BRAF, MAP2K1, and NRAS (Tiered sequencing for Noonan syndrome)
Effective January 1, 2017, all NGS panels are performed on an exome backbone with the potential for reflex to whole exome sequencing at a reduced cost. Please contact the laboratory to discuss the requirements for exome sequencing.
|Specimen Requirements||5 to 10 ml of peripheral blood collected in an EDTA (lavender top) Vacutainer tube is preferred. The minimal blood needed for reliable DNA isolation is 3 ml.|
|Transport||The specimen should be kept at room temperature and delivered via overnight shipping. FedEx is preferred. If shipment is delayed by one or two days, the specimen should be refrigerated and shipped at room temperature. Do not freeze the specimen. Samples collected on Friday can be safely designated for Monday delivery.|
|Turnaround time||8-10 weeks|
If the pathogenic mutation(s) are identified in an affected individual using this panel, prenatal diagnosis is available for future pregnancies. Sanger sequencing will be used for prenatal diagnosis when there is a known familial mutation. Additional fees for cell culture and maternal cell contamination may apply. Maternal cell contamination studies are required for all prenatal molecular tests. Contact the laboratory prior to sending a prenatal specimen.
Insurance billing is available for this test. The Insurance Billing Form is required along with copies of the authorization or letter of agreement from the insurance company.